Ivan Franko National University of Lviv, Kyryla and Mefodiya Str., 6, 79005, Lviv, Ukraine.
Ivan Franko National University of Lviv, Kyryla and Mefodiya Str., 6, 79005, Lviv, Ukraine; Institute of Cell Biology of National Academy of Sciences of Ukraine, Drahomanov St., 14/16., 79005, Lviv, Ukraine.
Eur J Med Chem. 2022 Nov 5;241:114633. doi: 10.1016/j.ejmech.2022.114633. Epub 2022 Aug 7.
The N-(4-thiocyanatophenyl)-1H-1,2,3-triazole-4-carboxamides were synthesized via the condensation of variety of 1H-1,2,3-triazole-4-carboxylic acids and 4-thiocyanatoaniline using CDI as amide coupling reagents. According to computer-aided calculations, all synthesized compounds are expected to have acceptable ADME profile for drug design. The antiproliferative potency of derivatives was evaluated towards different cell lines. The specific activity of four N-(4-thiocyanatophenyl)-1H-1,2,3-triazole-4-carboxamides (4a, 4b, 4c, 4f) was comparable to doxorubicin (GI = 0.65 μM) at nanomolar level against Jurkat cells in the range of GI 0.63-0.69 μM. According to the results of toxicity studies of the compounds for HEK293, HaCaT, Balb/c 3T3 cells, compound 4a was selected for further studies as a biocompatible agent with promising anticancer activity in the NCI60 cell lines. A remarkable antiproliferative activity of compound 4a towards leukemia cell lines (SR, MOLT-4; CCRF-CEM; HL-60(TB); K-562; RPMI-8226) was observed and high cytotoxicity towards the CAKI-1 (kidney cancer), LOX IMVI (melanoma) and UO-31 (renal cancer) cells lines was detected. Compound 4a inhibits LOX IMVI cells growth at a GI value of 0.15 μM. COMPARE analysis to indicate potential mechanisms of action of novel compound, as well as in silico SwissTargetPrediction and SwissSimilarity were performed. Compound 4a induced morphological changes (apoptotic bodies, membrane blebbing, chromatin condensation), and DNA fragmentation in Jurkat T-cells. It reduced mitochondrial membrane potential and induced DNA damage in Jurkat cells without binding and/or intercalation to DNA molecule.
N-(4-异硫氰基苯基)-1H-1,2,3-三唑-4-甲酰胺通过 1H-1,2,3-三唑-4-羧酸和 4-异硫氰酸苯胺的缩合反应合成，使用 CDI 作为酰胺偶联试剂。根据计算机辅助计算，所有合成的化合物预计具有可接受的药物设计 ADME 特性。衍生物的抗增殖活性针对不同的细胞系进行了评估。四种 N-(4-异硫氰基苯基)-1H-1,2,3-三唑-4-甲酰胺（4a、4b、4c、4f）的比活性与阿霉素（GI = 0.65 μM）相当，在纳摩尔水平对 Jurkat 细胞的 GI 值为 0.63-0.69 μM。根据化合物对 HEK293、HaCaT、Balb/c 3T3 细胞的毒性研究结果，选择化合物 4a 作为具有生物相容性和在 NCI60 细胞系中具有潜在抗肿瘤活性的候选药物进一步研究。化合物 4a 对白血病细胞系（SR、MOLT-4；CCRF-CEM；HL-60(TB)；K-562；RPMI-8226）表现出显著的抗增殖活性，并对 CAKI-1（肾癌）、LOX IMVI（黑色素瘤）和 UO-31（肾癌）细胞系表现出高细胞毒性。化合物 4a 以 GI 值 0.15 μM 抑制 LOX IMVI 细胞的生长。为了指示新型化合物的潜在作用机制，进行了 COMPARE 分析，以及计算机模拟的 SwissTargetPrediction 和 SwissSimilarity 分析。化合物 4a 诱导 Jurkat T 细胞发生形态变化（凋亡小体、膜泡化、染色质浓缩）和 DNA 片段化。它降低了 Jurkat 细胞中线粒体膜电位，并在不与 DNA 分子结合和/或插入的情况下诱导 DNA 损伤。
